DESCRIPTION. (Adapted from the application). The overall goal of in this project is to explore the genetic basis of Alzheimer's disease (AD), utilizing patients and select family members ascertained through the Clinical Core. DNA samples will be prepared from blood and screened for mutations or polymorphisms in known and putative AD genes, and then used in followup genetic analyses of "promising" chromosomal regions that have been previously or will be subsequently identified through our genome screen for novel AD genes. The applicant's laboratory's search for AD loci began in 1983 predominantly utilizing AD kindreds and other AD cases collected through the Center. More recently, over 500 small families, primarily sibling pairs and trios, have been collected from various sites through the NIMH Alzheimer's Genetics Initiative. This has resulted in a very large AD sample set. Over the past decade and a half, the applicants have utilized the ADRC and NIMH samples to isolate and characterize known AD genes and to localize and identify novel AD genes including the alpha-2-macroglobulin gene on chromosome 12. Their efforts have recently been fostered by the initiation of a collaboration with the NIH Center for Inherited Disease (CIDR) to expand a genome scan employing large-scale, high-throughput, automated genotyping on the NIMH set. This has effectively allowed for focus on genetic analyses of specific regions of interest and testing of putative AD genes in the ADRC and NIMH sample sets. The results of the genetic research program are to be made available to investigators in the ADRC in a confidential research setting. These studies will further understanding of the genetic risk factors and gene interactions involved in AD and provide new insights into molecular, biochemical, and clinical genotype-phenotype correlations in the neuropathogenesis of AD.